Insulin-like growth factor-1 (IGF-1) is a polypeptide that, in part, mediates the influence of growth hormone on normal development. However, IGF-1 is a mitogen, and in some experimental systems produces cell transformation and inhibits apoptosis. Thus, there are reasons to suspect IGF-1 of playing a role in carcinogenesis, and these suspicions were heightened by recent results from the Physicians' Health Study, which indicated a strong association between baseline levels of IGF-1 and the subsequent occurrence of prostate cancer. We propose to delve further into this question by conducting a nested case- control study among male enrollees in the Cardiovascular Health Study (CHS). The CHS is a cohort study of persons over 65 years of age residing in four communities in the U.S. which began in 1989. On the approximately 225 men in the cohort who developed prostate cancer through the end of 1999, and on an equal-size sample of other male enrollees matched to the cases on demographic characteristics, an aliquot of blood obtained prior to the time of the case's diagnosis will be obtained from frozen samples in the CHS Central Blood Laboratory. These aliquots will be thawed and assayed for: l) levels of IGF-1, IGF binding protein-3, and prostate-specific antigen (PSA); and 2) IGF-1 and IGF-1 receptor genotypes. Cases and controls will be compared for differences in levels and genotype of IGF- 1 and the genotypes of its receptor, adjusting for levels of IGF binding protein-3 and for other possible confounding factors identified in the rich CHS database. In analyses of cancer in relation to blood IGF-1 levels, particular attention will be given to the results in men with no evidence of prostate cancer at the time the blood specimen had been drawn, i.e., those with a normal PSA value. We believe that the large number of subjects, the availability of blood specimens that predate the presence of prostate cancer, and the incorporation of relevant genetic characteristics that have not previously been examined with respect to cancer risk will allow the proposed study to provide a rigorous test of an important hypothesis regarding the etiology of prostate cancer.